IL-15 is a cytokine critically involved in the pathogenesis of celiac disease (CeD), a T cell-mediated intestinal disorder induced by dietary gluten. In CeD, IL-15 upregulation in intestinal epithelial cells (IECs) is critical for the development of villous atrophy by inducing lymphokine killer activity in cytotoxic intraepithelial lymphocytes (IE-CTL), promoting their survival and expansion, and rendering them resistant to regulation by TGF-?. Furthermore, dysbiosis of the intestinal microbiota has been implicated in CeD pathogenesis, however how it contributes to disease has not been established. Importantly, it is thought that around 40% of adult CeD patients have a partial response to gluten-free diet and do not exhibit the restoration of normal mucosal architecture, and 5-10% of adult CeD patients develop cryptic or overt T cell lymphoma. Our central hypothesis is that overexpression of IL-15 in IECs as found in CeD promotes immunopathology because of its ability to upregulate histone deacetylase (HDAC) activity in IE-CTLs, which cannot be countered by butyrate producing microbiota because of the concomitant development of dysbiosis. The objective of this application is to determine how IL-15 can induce such a comprehensive pathogenic reprogramming of IE-CTLs. The rationale for this project is that its successful completion will provide unprecedented insight into the mechanisms by which dysbiosis contributes to the pathology and the molecular control of IL-15-induced immunopathology, and the understanding of how particular HDAC isoforms control the epigenetic landscape of IE-CTLs. The two aims are synergistic but independent, employing the complementary advantages of studies in human and mouse, respectively. The proposed hypothesis will be tested by pursuing the following specific aims: 1) Characterizing the role of HDAC in the transcriptional and functional programs directed by IL-15 and inflammatory CeD mucosa in IE-CTL. 2) Characterizing the interplay between IL-15 and the microbiota on the reprogramming of IE-CTLs. The proposed research is innovative because it employs cutting-edge genome-wide approaches to reveal novel molecular mechanisms controlling IL-15 induced effector program and epigenetic modifications in IE-CTL. Its scope is wide-ranging because IL-15 is also thought to play a critical role in inflammatory bowel disease, organ-specific autoimmunity, large granular lymphocytic leukemia and enteropathy-associated T cell lymphoma. It will have a significant positive impact on human health because it will help define prophylactic and curative strategies that have the potential to reverse the pathogenic effects of IL-15.